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Journal of Viral Hepatitis, 2010, 17, 6576

doi:10.1111/j.1365-2893.2009.01153.x

Longitudinal evaluation of viral interactions in treated HIV-hepatitis B co-infected patients with additional hepatitis C and D virus
A. Boyd,1 K. Lacombe,1,2 P. Miailhes,3 J. Gozlan,4,5 P. Bonnard,6 J.-M. Molina,7 C. LascouxCombe,8 L. Serfaty,9 E. Gault,10,11 M. Desvarieux1,12 and P.-M. Girard1,2 1INSERM, Paris and UMR-S707,
Universite Pierre et Marie Curie-Paris6, Paris, France; 2Service de Maladies Infectieuses et Tropicales, Hopital Saint-Antoine, AP-HP, Paris, France; 3 Hospices Civils de Lyon, Hotel Dieu, Service dHepatologie et de gastroenterologie, Lyon, France; 4Service de Virologie, Hopital Saint-Antoine, AP-HP, Paris, France; 5UMRS 872, Centre de recherche des Cordeliers, Paris, France; 6Service de Maladies Infectieuses et Tropicales, Hopital Tenon, AP-HP, Paris, France; 7Service de Maladies Infectieuses et Tropicales, Hopital Saint-Louis, AP-HP, Paris, France; 8Service de Medecine Interne, Hopital Saint ` Louis, AP-HP, Paris, France; 9Service dHepatologie, Hopital Saint-Antoine, AP-HP, Paris, France; 10Service de Bacteriologie-Virologie-Hygiene, Hopital Avicenne, AP-HP, Bobigny, France; 11Universite Paris 13, EA-3604, Bobigny, France; and 12Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA Received December 2008; accepted for publication March 2009

SUMMARY. Virological interactions of hepatitis B (HBV),

hepatitis C (HCV) and hepatitis D (HDV) viruses in HIVinfected patients have been poorly characterized especially under treatment inuences. Undetection rates of hepatitis viruses were longitudinally analyzed in a 3-year cohort of 308 HIVHBV co-infected patients and compared using Generalized Estimating Equation models adjusted for age, HIV-RNA, CD4 cell-count and antiviral treatment. Chronic hepatitis co-infection in HIV-infected patients (age years, SD) was: 265 HBV (40.7, 8.2); 19 HBVHCV (39.7, 4.1); 12 HBVHDV (35.2, 9.9); 12 HBVHCVHDV (39.2, 5.2). At inclusion, treatment with lamivudine/tenofovir was not signicantly different between co-infection groups. HBV suppression was signicantly associated with HDV (aOR = 3.85, 95%CI 1.1313.10, P = 0.03) and HCV tri-infection (aOR = 2.65, 95%CI 1.036.81, P = 0.04), but marginally

associated with HIVHBVHCVHDV (aOR = 2.32, 95%CI 0.945.74, P = 0.07). In quad-infection, lower HDVundetectability (vs HIVHBVHDV, P = 0.2) and higher HCV-undetectability (vs HIVHBVHCV, P = 0.1) were demonstrated. The degree of HBV suppression varied between visits and co-infection groups [range of aOR during follow-up (vs HIVHBV co-infection): HIVHBV HCV = 2.235.67, HIVHBVHDV = 1.5315.17]. In treated co-infected patients, HDV expressed continuous suppression over HCV- and HBV-replications. Peaks and rebounds from undetectable hepatitis B, C and/or D viremia warrant closer follow-up in this patient population. HDVreplication was uncontrolled even with antiviral treatment. Keywords: hepatitis B virus, hepatitis C virus, hepatitis D virus, human immunodeciency virus, viral replication.

INTRODUCTION
Because of the similar modes of transmission, co-infection with human immunodeciency virus (HIV), hepatitis B (HBV), C (HCV) and/or D (HDV) occurs relatively frequently [13]. In HIVHBV co-infected patients, the additional effect
Abbreviations: GEE, General Estimating Equation; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HIV, human immunodeciency virus. Correspondence: Dr Karine Lacombe, MD PhD, Service de maladies infectieuses et tropicales, Hopital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France. E-mail: karine. lacombe@sat.aphp.fr

of HCV and HDV on liver brosis has been associated with a myriad liver-related complications, such as increased risk of hepatic decompensation and cirrhosis [46]. To decrease these morbidities, treatment strategies are aimed at reducing viral replication, which can be complicated by the patients treatment response, virological mutations and interactions between hepato-tropic viruses. Studies on viral interactions in the context of HIV have predominately included HBV and HDV co-infected patients, resulting in conicting conclusions. Some cross-sectional studies suggest that the inhibition effect of HDV on HBV, typically seen in non HIV-infected patients, is no longer apparent with HIV-infection [79]. By contrast, a larger study found that both HBV and HCV replication were suppressed in

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A. Boyd et al. visit. This research project was approved by the Pitie ` Salpetriere hospital ethics committee (Paris, France) and written informed consent was obtained from all patients.

the presence of additional HDV-infection [1]. This nding was also supported in a clinical trial for interferon therapy in patients with nonadvanced stages of HIV [10]. Similarly, Sheng et al. [6] reported a lower HBV replication rate at inclusion under HDV infection, which might have been sustained in a follow-up of HIVHBV co-infected patients when no HBV genotypic resistance to lamivudine had developed. In the context of HIV, very little is also understood concerning viral interactions of hepatitis viruses over time. This is all more important as Raimondo et al. observed more complicated viral dynamics during the course of viral hepatitis replication in HIV-seronegative patients, demonstrating that uctuations can occur between HBV, HCV or both [11]. Similar reciprocal interactions between HBV and HCV have also been reported in ve HIVHBVHCV infected patients [12]. In both cases, these uctuations were reported on populations studied prior to the availability of antiviral treatments, such as lamivudine, adefovir and tenofovir, therefore allowing no conclusions in the current context of antiviral treatment. Finally, dynamic interactions have not been determined in the HIV-positive population within the context of a prospective cohort study allowing for comparison of multiple viral interactions during an overall period of time [12]. The aim of the longitudinal study presented herein was to examine, among HIVHBV infected patients additionally co-infected with HCV and/or HDV, the interactions between viral hepatitis, the impact of HIV-disease and of antiviral treatment during follow-up. Particular attention was further given to the relationship between antiviral treatment and viral replication assessed within HBV, HCV and HDV virological proles.

Virological data
Viral loads of HIV and all chronic hepatitis viruses were obtained at inclusion and every 12 months during follow-up. HIV-1 viral loads were measured using either a branchedDNA (b-DNA Quantiplex 3.0, detection limit: 50 copies/mL, Bayer Diagnostics, Cergy Pontoise, France) or real-time PCR technique (COBAS AmpliPrep/COBAS TaqMan HIV-1 Test, detection limit: 40 copies/mL, Roche Molecular Systems, Meylan, France) [between test correlation = 0.969] [14]. HBV viral loads were quantied with commercial PCRbased assays (COBAS AmpliPrep/COBAS TaqMan HBV Test, detection limit: 12 IU/mL; COBAS Amplicor HBV Monitor Test, detection limit: 600 IU/mL, Roche Diagnostic Systems) [between test correlation = 0.966] [15]. When antibodies to hepatitis C or D virus were detected, serum HCV-RNA and/or HDV-RNA were quantied. HCVRNA viral loads were determined using the following methods (between test correlation vs Abbott RealTime HCV): PCRbased assay [Cobas Amplicor HCV Monitor v2.0, detection limit: 60 IU/mL, (r = 0.81); COBAS AmpliPrep/COBAS TaqMan HCV, detection limit: 10 IU/mL (r = 0.83), Roche Diagnostic Systems; Abbott RealTime HCV, detection limit: 12 IU/mL, Abbott Molecular Inc., Des Plaines, IL, USA], branched-DNA technique [VERSANT HCV 3.0, detection limit: 615 IU/mL, Bayer Diagnostics (r = 0.98)] or in certain undetectable viral loads, a qualitative, transcription-mediated amplication test [VERSANT HCV-RNA Qualitative (TMA), detection limit: 10 IU/mL, Bayer Diagnostics (sensitivity = 95.0%, specicity = 99.6%)] [16,17]. HCV genotypes were determined with a commercial line probe assay (InnoLipa HCV, Innogenetics, Zwijnaarde, Belgium). HDV-RNA quantications were performed for each patient, from serum aliquots kept frozen at )80 C, using a real-time quantitative PCR assay (sensitivity threshold: 1000 copies/ mL) [18]. HDV genotype was determined by phylogenetic analysis of the amplied R0 region of the genome (nucleotides 8851285) as previously described [19]. Because of the advancement of viral load quantication techniques during the 3-year follow-up, several detection thresholds were used. A standard detection limit was employed in aims to establish uniformity across tests in which undetectable viral loads were dened for HIV (250 copies/mL), HBV (600 IU/mL) and HCV (615 IU/mL). Viral undetectability is herein dened as a viral load that is undetectable below these thresholds.

PATIENTS AND METHODS Patients and study design


The study design has been described previously [13]. Briey, 308 HIVHBV co-infected patients were enrolled in a cohort study determining risk-factors of liver brosis. Patients were recruited at seven clinical centres from May 2002 to May 2003 and followed for 36 months. Inclusion criteria included a positive HBs antigen test and two positive HIV ELISA tests with a full Western blot at least 6 months prior. Patients were also tested for the presence of antibodies to hepatitis C and D at inclusion and every 12 months thereafter. Four mutually exclusive comparison groups were dened per positive concordant serology 6 months prior to each time-point: (i) HIVHBV, (ii) HIVHBVHCV, (iii) HIV HBVHDV and (iv) HIVHBVHCVHDV. Demographical information (age, sex, mode of transmission and country of origin) was taken at study inclusion. Duration of HIV and HBV infection was estimated from the rst positive serology. Treatment information specic to HIV and HBV was taken at inclusion and during each follow-up

Statistical analysis
Means (SD) and frequencies (percentages) related to patient population characteristics and median (IQR) durations of 2009 Blackwell Publishing Ltd, 17, 6576

Hepatitis Viral Interactions in HIV antiviral treatment prior to inclusion were calculated for each group of co-infection. Groups were compared using a two-tailed t-test with least square means for continuous variables and continuity chi-square or Fishers Exact test for categorical variables. As viral load measurements were repeated for each patient, a General Estimating Equation (GEE) [20] with an exchangeable working correlation was used to model the overall effect of co-infection group on standard detection rates of HBV, HCV and HDV during the 3-year follow-up. GEE models were adjusted for age, indicators relating to the degree of HIV disease (serum HIV-RNA <250 copies/mL and CD4+ cell count >200 cells/mm3), and antiviral treatment. These models perform adjustment with information provided at each 12-month visit and report an overall OR of detection differences in patients with and without a particular covariate. Treatment exposures implying a greater impact on undetectibility prior to each visit were selected as concurrent treatment with lamivudine/emtricitabine, concurrent adefovir/tenofovir and prior and current treatment with interferon and/or peg-interferon (also including ribavirin). Antiviral resistance was not modelled in the equation because of the lack of sufcient information. In order to examine the overall differential impact of time on replication, an interaction term dened as the product between follow-up time and co-infection group was added to each GEE model above and tested using a Wald chi-square test. The consistency of the time-dependent effects was also assessed using odds ratios calculated by logistic regression models at each time-point adjusted for the same variables as in the GEE models. Differences in HIV-RNA detection between co-infection groups were modelled using similar GEE methods adjusted for viral detection of hepatitis viruses (HBV-DNA, HCV-RNA or HDV-RNA in separate equations), CD4+ cell count >200 cells/mm3, and antiretroviral treatment (concurrent treatment with NRTI, NNRTI and PI classes). In patients who lost HBsAg, visits during and after which patients seroconverted HBsAg negative were excluded from analysis. All statistical analyses were performed using SAS v 9.1.3 (SAS Institute Inc., Cary, NC, USA) and stata v 9.0 (StataCorp, College Station, TX, USA) statistical packages. All signicances were determined by a P-value of less than 0.05.

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tenofovir respectively. No signicant treatment differences were found between co-infection groups, except for interferon, which was more likely to be administered in patients with additional HDV co-infection (P = 0.02). No differences in the number of patients with detectable HIV-RNA were found at inclusion between co-infection groups [overall HIV detection: 119/308 (38.6%)]. HBV-DNA detection was signicantly lower in patients infected with HCV and/or HDV vs HIVHBV at inclusion (P = 0.001) and the number of patients (%) with detectable HBV for each co-infection groups was as follows: 147 (55.5), 7 (36.8), 1 (8.3) and 4 (33.3). Eleven (61.1%) patients with HIVHBV HCV tri-infection had detectable levels of HCV-RNA vs 2 HIV HBVHCVHDV (20.0%) quad-infected patients (P = 0.05). In HIVHBVHDV and HIVHBVHCVHDV co-infections, HDV-RNA detection was found in 7 (63.6%) and 9 (81.8%) patients respectively (P = 0.6). At inclusion, the proportion of HBeAg-positive patients was lower in additional HDV co-infection [7 (29.2%) with HIVHBVHDV and HIVHBVHCVHDV vs 153 (53.9%) in HIVHBV and HIVHBVHCV co-infection, P = 0.02]. During an average of 33-months of follow-up per patient (total of 847.6 person-years), HBeAg seroconversion occurred in 40 patients (13.0%) and seven patients initially antiHBeAb positive reverted to HBeAg positive. During the same period, eight patients became HBsAg-negative (seven HIVHBV and 1 HIVHBVHCV co-infected). HBs and HBe seroconversion rates did not differ between co-infection groups (P = 0.7 and 0.6 respectively).

Virological interactions of HBV, HCV and HDV


General Estimating Equation models with adjusted ORs for undetectablilty of HBV, HCV and HDV replications, including multivariable factors potentially inuencing viral replication, are found in Table 2. In HIVHBVHCV tri-infection, HBV replication was signicantly attenuated when compared with HIVHBV co-infection after adjusting for age, indicators relating to the degree of HIV disease and antiviral treatment (aOR for undetectability = 2.65, 95%CI: 1.036.81, P = 0.04). In further multivariable adjustments at each time point, the degree to which HBV was suppressed somewhat varied between visits (range of adjusted OR during follow-up: HIV HBVHCV vs HIVHBV = 2.235.67). Similarly, HBV-replication was signicantly reduced in the presence of HIVHBVHDV vs HIVHBV co-infection after adjustment (aOR = 3.85, 95%CI: 1.1313.10, P = 0.03). Furthermore, a larger contrast in suppression was found between visits in the context of this tri-infection (range of adjusted OR during follow-up: HIVHBVHDV vs HIV HBV = 1.5315.17). In quad-infection, the suppressive effect of HDV and HCV individually on HBV-replication was slightly abated, however still demonstrating an overall higher adjusted

RESULTS Study population characteristics


The total number of patients in each co-infection group was as follows: 265 HIVHBV, 19 HIVHBVHCV, 12 HIV HBVHDV and 12 HIVHBVHCVHDV. The major demographic characteristics are found in Table 1 along with group-by-group comparisons. Over 80% of all patients were treated before inclusion with combined antiretroviral therapy (cART) and/or lamivudine. 5.5% and 17.5% of all patients included in their treatment regimen adefovir or 2009 Blackwell Publishing Ltd , 17, 6576

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Table 1 Description of the study population according to viral hepatitis subgroups at inclusion HIVHBV (n = 265) Demographics Sex ratio males/females (% males) Age years, mean (SD) HIV Infection Estimated duration of HIV infection years, mean (SD) CD4+ cell count per mm3, means (SD) Nb (%) of patients treated with cART before inclusion Nb (%) of patients treated with tenofovir before inclusion Duration of tenofovir before inclusion months, median (IQR) Viral hepatitis Estimated duration of HBV infection years, mean (SD) Nb (%) of patients treated with lamivudine before inclusion Duration of lamivudine before inclusion months, median (IQR) Nb (%) of patients treated with adefovir before inclusion Duration of adefovir before inclusion months, median (IQR) Nb (%) of patients treated with interferon before inclusion Nb (%) of patients treated with interferon/ribavirine before inclusion HBV serological markers HBeAg n (%) anti-Hbe Ab n (%) Nb (%) of Pre core mutants (W28 mutation) (n = 205) Nb (%) of YMDD mutants (n = 189) HIVHBVHCV (n = 19) HIVHBVHDV (n = 12) HIVHBVHCV HDV (n = 12)

Test Sign

224/41 (84.5) 40.7 (8.2)a 8.6 (5.5)a 445 (262) 241 (90.9) 49 (18.5)

16/3 (84.2) 39.7 (4.1)ab 13.5 (3.9)b 413 (235) 18 (94.7) 2 (10.5)

8/4 (66.7) 35.2 (9.9)b 8.1 (6.4)a 414 (135) 11 (91.7) 0

11/1 (91.7) 39.2 (5.2)ab 13.4 (5.4)b 297 (155) 11 (91.7) 3 (25.0)

1 3 3 3 1 1

ns * * ns ns ns

4.4 (1.78.6)

9.7 (4.215.2)

3.2 (1.85.7)

ns

7.0 (5.6)a 217 (81.9)

9.9 (6.9)b 17 (89.5)

7.1 (6.1)ab 10 (83.3)

9.7 (8.8)ab 12 (100)

3 1

* ns

51.3 (25.271.2) 57.7 (34.769.9) 31.8 (16.758.8) 60.4 (16.373.8) 3

ns

14 (5.3)

1 (5.3)

2 (16.7)

ns

7.6 (4.79.5)

7.9

11.0 (8.913.2)

ns

48 (18.1)a

3 (15.8)ab

4 (33.3)ab

5 (41.7)b

1, 2

1 (5.6)

145 (54.7) 114 (43.0) 52/187 (27.8)a 120/173 (69.4)

8 (42.1) 10 (52.6) 2/8 (25.0)ab 7/8 (87.5)

4 (33.3) 7 (58.3) 5/6 (83.3) 1/4 (25.0)

3 (25.0) 8 (66.7) 1/4 (25.0) 2/4 (50.0)

1, 2 1, 2 1 1

ns ns

ab

ns

Means were compared horizontally between co-infected groups. For each comparison, means or numbers with different letters indicate signicant differences (P < 0.05), while those sharing the same letter are indistinguishable. Tests used to determine signicance: (1) Pearsons continuity chi-square test; (2) Fishers Exact Test; (3) multiple two-tailed t-test using least square means. Sign: *Presence of a signicant difference (P < 0.05) between groups. ns: no signicance found between any co-infected group.

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Table 2 Impact of viral replication, HIV disease indicators and antiviral treatment on HBV, HCV and HDV undetectability HBV-DNA undetectability (<600 IU/mL) aOR 95%CI * (1.036.81) (1.1313.10) (0.945.74) (1.473.06) (1.001.05) (1.092.84) (0.651.46) (0.6548.86) (0.581.14) (0.911.11) (0.261.23) (0.865.14) (0.581.32) (1.0711.66) 0.1 0.2 0.9 0.2 0.1 0.5 0.04 (2.274.63) (0.614.07) 0.3 3.53 <0.001 0.88 * * * 0.04 0.03 0.07 <0.001 0.06 0.02 0.9 N/A 1.00 N/A 5.65 0.81 1.01 0.57 2.10 P-value 95%CI P-value 1.00 2.65 3.85 2.32 2.12 1.03 1.76 0.97 3.24 1.58 aOR aOR N/A N/A 1.00 0.30 1.03 1.00 0.31 1.15 0.68 1.41 HCV-RNA undetectability (<615 IU/mL) HDV-RNA undetectability (<1000 copies/mL) 95%CI P-value

2009 Blackwell Publishing Ltd , 17, 6576 * (0.042.24) (0.293.69) (0.881.15) (0.052.09) (0.403.26) (0.212.20) (0.603.29) * 0.2 0.9 0.9 0.2 0.8 0.5 0.4

Co-infection group HIVHBV (n = 265) HIVHBV with HCV (n = 19) HIVHBV with HDV (n = 12) HIVHBV with HCVHDV (n = 12) Serum HIV-RNA <250 copies/mL Age (by year) CD4+ lymphocytes >200 cells/mm3 Concurrent treatment with lamivudine or emtricitabine Concurrent treatment with adefovir or tenofovir Prior and current treatment with standard and/or pegylated interferon

Hepatitis Viral Interactions in HIV 69

*Denotes the reference group. Multivariable GEE models were adjusted for age, indicators of HIV-infection (serum HIV-RNA >250 copies/mL and CD4+ cell count >200 cells/mm3) and anti-hepatic viral treatment (concurrent treatment with lamivudine or emtricitabine, concurrent treatment with adefovir or tenofovir and prior and current treatment with interferon and/or peg-interferon). The number of each co-infection group at inclusion. Four HIVHBV co-infected patients seroconverted to either HCV (n = 2) or HDV (n = 2) during follow-up. N/A: not applicable.

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A. Boyd et al. missing data on treatment or viral loads during follow-up (HIVHBV n = 179, HIVHBVHCV n = 14, HIVHBV HDV n = 7, HIVHBVHCVHDV n = 4). Co-infected patients presented four viral replication proles for hepatitis B, C and D viruses: [1] pre-controlled or controlled proles patients with undetectable viral loads because of treatment initiated before and/or during follow-up [2], blipped proles patients with undetectable viremia that reverted to detectable and then undetectable [3], rebounded proles patients with undetectable viral loads that then became detectable, and [4] uncontrolled patients with constantly detectable viral loads. Examples of these replication proles are shown in Fig. 1. The most common antiviral treatments taken during follow-up were lamivudine or emtricitabine and tenofovir: 113 (63.1%) HIVHBV, 12 (85.7%) HIVHBVHCV, 5 (71.4%) HIVHBVHDV and 3 (75.0%) HIVHBVHCVHDV. Proles are presented in Table 4 for each co-infection group by the corresponding HBV prole class. HIVHBV and HIVHBVHCV co-infections exhibited more stable proles under treatment, in which 78.2% (151/193) of HBV and 57.1% (8/14) of HCV proles were either pre-controlled or controlled. The stability of HBV and HCV proles was still apparent in HIVHBVHDV and HIVHBVHCVHDV co-infections, with a majority of HBV (7/11, 63.6%) and HCV (3/4, 75%) proles presenting pre-controlled or controlled replication. By contrast, the greater part of HDV proles, regardless of co-infection group, either blipped or were uncontrolled (7/11, 63.6%).

proportion of patients with undetectable HBV (HIVHBV HCVHDV vs HIVHBV: aOR = 2.32, 95%CI: 0.945.74, P = 0.07). This effect was strongest at inclusion and 12month visits (aOR = 3.24 and aOR = 7.89 respectively) however disappeared at the 24- and 36-month visits (aOR = 0.78 and aOR = 1.78 respectively). The adjusted odds of patients having undetectable HCVRNA were 5.65-fold higher (95% CI: 0.6548.86, P = 0.1) in HIVHBVHCVHDV co-infected patients compared with HIVHBVHCV. Conversely, the adjusted HDV-RNA undetectability odds tended to be lower in HIVHBVHCVHDV infection compared with HIVHBVHDV (aOR = 0.30, 95%CI: 0.042.24, P = 0.2). Adjusted odds of undetectable HCV- and HDV-RNA showed little variation between individual visits, supported by nonsignicant, time-dependant interaction terms including HCV and HDV co-infection groups (P = 0.3 and P = 0.7 respectively). Indicators of HIV disease and concurrent treatment with adefovir or tenofovir (but not interferon) were also associated with HBV-DNA undetectability (Table 2). Treatment with interferon and ribavirin signicantly increased the adjusted odds of HCV-RNA undetectability (aOR = 3.53, 95%CI: 1.07 11.66, P = 0.04). No factors emerged as signicantly impacting the adjusted odds of HDV-RNA undetectability during the overall study period including treatment with lamivudine/emtricitabine or adefovir/tenofovir, which also did not signicantly inuence HCV undetectability (Table 2).

Determinants of HIV-replication
Table 3 describes the adjusted determinants of HIV-RNA undetectability during overall follow-up in three separate models with respect to HBV, HCV and HDV replications. In HBV replication, the proportion of patients with undetectable HIV-RNA signicantly decreased in only HIVHBVHCV triinfection vs HIVHBV (aOR = 0.45 95%CI: 0.220.92; P = 0.03) after adjustment for HBV viral detection, CD4+ cell count >200 cells/mm3 and antiretroviral treatment. In HCV and HDV replications, there were no signicant differences in HIV-detection rates between HIVHBVHCVHDV vs HIV HBVHCV (aOR = 1.81; 95%CI: 0.506.52; P = 0.4) and vs HIVHBVHDV (aOR = 0.91; 95%CI: 0.155.42; P = 0.9). In the multivariable models with respect to HBV and HCV replication, higher CD4+ cell count was independently associated with an increased probability of undetectable HIV-RNA (P < 0.001 and P = 0.02 respectively). The presence of antiretroviral therapy was also signicantly associated with lower HIV detection rates in HBV and HDV models, yet in HCV replication, NRTI-based therapy was only borderline signicant (aOR = 6.24; 95%CI: 0.9740.24, P = 0.05).

DISCUSSION
We report the longest prospective cohort data on viral interactions in HIV-infected subjects co-infected with hepatitis B, C and/or D viruses to-date. We also report the rst longitudinal data on the impact of treatment on both chronic hepatitis replication and HIV. Over an average follow-up of 33 months per patient, co-infection with HDV and/or HCV, low HIV viral load, higher CD4 counts and concurrent treatment with adefovir or tenofovir stood as independent determinants of HBV-DNA undetectability, conrming cross-sectional or retrospective data on the subject [1,2128]. Co-infection with HDV emerged as a determinant of HCV-RNA undetectability, yet not statistically signicant, considering the small number of patients in the quad-infected group (n = 12). Interferon-based treatment (prior or current) with ribavirin was the strongest determinant of HCV-RNA undetectability. No clinical, biological or therapeutic factor seemed to inuence HDV-RNA undetectability cumulatively during the entire follow-up period. Valuable insight is given on hepatic viral interactions when HBV-DNA replication is additionally suppressed by treatment (especially by ADV and/or TDF as indicated by the GEE model). The uctuating and generally reciprocal replication of HBV and HCV [11,12,26] was greatly altered, 2009 Blackwell Publishing Ltd, 17, 6576

Treatment inuence on chronic hepatitis detection proles


Proles of viral replication in the presence of antiviral treatment were examined on a subset of patients with no

Table 3 Impact of hepatitis virus interactions, HIV disease indicators and antiretroviral treatment on HIV undetectability (<250 copies/mL) HIV-RNA undetectability in respect to HBV-DNA replication aOR 95%CI P-value 95%CI P-value aOR HIV-RNA undetectability in respect to HCV-RNA replication HIV-RNA undetectability in respect to HDV-RNA replication aOR 95%CI P-value

2009 Blackwell Publishing Ltd , 17, 6576 1.00 0.45 0.50 1.17 3.59 2.82 15.20 3.30 2.65 * (0.506.52) (1.178.90) (0.191.66) (0.9740.24) (0.7314.45) (0.252.11) * (0.220.92) (0.211.18) (0.403.45) (2.056.30) (1.914.16) (6.5035.57) (1.766.17) (1.594.43) * 0.03 0.1 0.8 <0.001 <0.001 <0.001 <0.001 <0.001 N/A 1.00 N/A 1.81 3.23 0.56 6.24 3.25 0.73 * 0.4 0.02 0.3 0.05 0.1 0.6 N/A N/A 1.00 0.91 1.81 0.65 6.24 7.13 6.74 * (0.155.42) (0.398.38) (0.085.10) (1.1932.76) (0.28180.19) (1.1938.16) * 0.9 0.4 0.7 0.03 0.2 0.03

Co-infection group HIVHBV (n = 265) HIVHBV with HCV (n = 19) HIVHBV with HDV (n = 12) HIVHBV with HCVHDV (n = 12) CD4+ lymphocytes >200 cells/mm3 Serum HBV-DNA <600 IU/mL Concurrent treatment with NRTI Concurrent treatment with NNRTI Concurrent treatment with PI

*Denotes the reference group. Multivariable GEE models were adjusted for viral detection of hepatitis viruses (HBV-DNA, HCV-RNA or HDV-RNA in separate equations), CD4+ cell count >200 cells/mm3 and antiretroviral treatment (concurrent treatment with NRTI, NNRTI and PI classes). The number of each co-infection group at inclusion. Four HIVHBV co-infected patients seroconverted to either HCV (n = 2) or HDV (n = 2) during follow-up. N/A: not applicable.

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8.0
3TC 250.0 ADV TDF Peg-IF

(a) 8.0

(b) 10.0 log10 copies/mL HDV RNA

10.0

3TC 400.0 TDF Peg-IF

log10 Ul/mL HCV RNA

log10 Ul/mL HBV DNA

log10 Ul/mL HBV DNA

6.0

6.0

200.0

8.0

8.0

300.0 ALT Ul/mL ALT Ul/mL

150.0 4.0 100.0 2.0

ALT Ul/mL

6.0

6.0 200.0 4.0 100.0

4.0

4.0

2.0

50.0

2.0

2.0

0.0

0.0 0 12 24 Months 36 HCV VL

0.0

0.0

0.0 0 12 24 Months 36 HDV VL

0.0

HBV VL ALT level

HBV VL ALT level

(c) 8.0

3TC ADV

250.0 200.0 150.0 100.0 50.0 0.0 ALT Ul/mL

(d) 10.0 log10 copies/mL HDV RNA

8.0

8.0

3TC 250.0 TDF Peg-IF

log10 Ul/mL HBV DNA

log10 Ul/mL HCV RNA

6.0

6.0

log10 Ul/mL HBV DNA

6.0

8.0

6.0

200.0

150.0

4.0

4.0

4.0 100.0

4.0

2.0

2.0

2.0

2.0

50.0

0.0 0 12 24 Months 36 ALT level

0.0

0.0

0.0 0 12 24 Months 36 HCV VL ALT level

0.0

HBV VL

HBV VL HDV VL

Fig. 1 Examples of treatment-response proles. Viral loads at each of the 12-month visits are presented in the gure above. The antiviral treatments (3TC lamivudine, ADV adefovir, TDF tenofovir and Peg-IF pegylated interferon) over follow-up are listed above and a range of dots indicates the time period under which a patient received treatment. Horizontal lines have been drawn to identify the standardized detection limit for HBV-DNA (<600 IU/mL dashed line), HCV-RNA (615 IU/mL dotted line), and HDV-RNA (1000 copies/mL solid line). (a) Example of an HBV and HCV controlled treatment-response prole found in an HIVHBVHCV tri-infected patient with controlled HBV after 12 months of treatment. HCV became controlled 24 months after HBV. This patient seroconverted to HBeAg-negative and anti-HBeAb-positive at the 12-month visit. (b) Example of an HBV blipped and HDV uncontrolled treatment-response prole exhibited in an HIVHBVHDV tri-infected patient with pre-controlled HBV from treatment with lamivudine prior to inclusion. HBV viremia became detectable and blipped at the 12-month visit. HDV-RNA was uncontrolled, even under treatment. This patient was HBeAgnegative throughout follow-up. (c) Example of a rebounding HBV treatment-response prole in which HBV-DNA became undetectable at month 12 then rebounded at the 36-month visit. This HIVHBV co-infected patient seroconverted AgHBe(+) at the 12-month visit. (d) Example of an HBV, HCV controlled and HDV blipped treatment-response prole. HBV was controlled 24-months prior to HCV in an HIVHBVHCVHDV quad-infected patient under treatment with lamivudine, tenofovir and pegylated-interferon. HDV had a prolonged blip at the 12- and 24-month visits. This patient seroconverted HBeAg-negative at the end of follow-up. rendering HCV infection dominant in both the GEE and virological proling methods for HIVHBVHCV tri-infection even under interferon therapy. HDV was continually dominant over HBV replication in HIVHBVHDV vs HIV HBV infection. Unfortunately, it is difcult to identify the individual effects on viral suppression from HDV, namely the inhibitory effect via delta antigen [29], and treatment. Most interestingly, the degree to which HCV and/or HDV suppressed HBV replication varied considerably over follow-up, even in the presence of treatment. For example, the adjusted proportion of undetectable HBV changed from 15 to 2-times higher in HIVHBVHDV and from 2 to 6-times higher in HIVHBVHCVHDV vs HIVHBV co-infection within a 24-month span. In slight contrast, HBV inhibition was 2009 Blackwell Publishing Ltd, 17, 6576

Table 4 Treatment response proles according to co-infection group and HBV prole

HBV prole HBV blipped n (%) Other hepatic prole(s) ** w/HCV pre-controlled w/HCV rebounded w/HCV uncontrolled w/HDV controlled w/HDV uncontrolled 0 0 0 0 0 0 w/HCV rebounded w/HCV uncontrolled 0 w/HCV pre-controlled 7 (3.9) ** 22 (12.3) 1 (7.1) 0 0 0 1 (14.3) 0 0 Other hepatic prole(s) 11 (6.1) 1 (7.1) 0 0 1 (14.3) 0 0 1 (25.0) w/HCV controlled and HDV blipped w/HCV controlled and HDV uncontrolled w/HCVHDV uncontrolled 0 n (%) n (%) HBV rebound HBV uncontrolled Other hepatic prole(s) ** w/HCV pre-controlled w/HCV rebounded w/HCV uncontrolled w/HDV pre-controlled or controlled w/HDV uncontrolled

HBV pre-controlled and controlled

2009 Blackwell Publishing Ltd , 17, 6576 w/HDV pre-controlled or controlled w/HDV uncontrolled 1 (25.0) w/HCV controlled and HDV blipped w/HCV pre-controlled/ controlled and HDV uncontrolled w/HCVHDV uncontrolled 0 w/HCV controlled and HDV blipped w/HCV pre-controlled/ controlled and HDV uncontrolled w/HCVHDV uncontrolled

n (%)

Other hepatic prole(s)

HIVHBV (n = 179) 139 (77.6) ** HIVHBVHCV (n = 14) 6 (42.0) w/HCV pre-controlled or controlled 1 (7.1) w/HCV rebounded 5 (35.7) w/HCV uncontrolled HIVHBVHDV (n = 7) 3 (42.9) w/HDV pre-controlled or controlled 2 (28.6) w/HDV uncontrolled HIVHBVHCVHDV (n = 4) 1 (25.0) w/HCV controlled and HDV blipped 1 (25.0) w/HCV pre-controlled and HDV uncontrolled

w/HCVHDV uncontrolled

Hepatitis Viral Interactions in HIV 73

Summary of replication proles for each hepatitis virus: pre-controlled or controlled proles patients with undetectable viral loads because of treatment initiated before and/or during follow-up, blipped proles patients with undetectable viremia that reverted to detectable and then undetectable, rebounded proles patients with undetectable viral loads that then became detectable and uncontrolled patients with constantly detectable viral loads. **Not applicable.

74

A. Boyd et al. be more uncontrollable in HIVHBVHCV compared with HIVHBVHCVHDV infection, which may be attributed to the high proportion of patients (9 of 15) with a difcultto-treat, HCV genotype 1. By in large, HDV-replication remained uncontrolled regardless of co-infection group. Even treatment that inhibits HBV replication, such as Tenofovir, does not appear to be as effective in hindering HDV viral replication in our study population. By contrast, recent data suggest that the use of nucluos(t)ides analogues against HBV in HIVHBVHDV tri-infected patients may decrease HDV replication [44]. However, HDV-RNA levels inefciently declined with lengthy periods of antiviral treatment and factors such as HBsAg clearance appeared more likely to promote undetectable levels of HDV-RNA. One limitation of this study is the length of the 12-month intervals at which the viral load may have transitioned from being detectable to undetectable, especially in the case of viral resistance to nucleoside analogues. However, this problem may have been mitigated by the high-number of patients with mutations indicating antiviral resistance (i.e. YMDD and pre core) at inclusion and the increasing numbers of patients treated with ADV or TDF (with small mutation probability [45]) during follow-up. Second, although our cohort is one of the largest of co-infected subjects, we recognize that the number of patients might have limited our power for some subgroups. On the other hand, this gives us condence that when statistically signicant results emerged, the postulated effect is likely to be robust. Given the increasing availability of treatment, however, we trust that our cohort may constitute one of the last opportunities to examine viral replication including untreated patients. Third, the serological basis of HCV and HDV infection, upon which our co-infection groups were determined, do not take into account the difference between chronic or cured HCV or HDV infections. However, some patients did have nonreplicating viral hepatitis at inclusion, which later rebounded and/or blipped during follow-up. Excluding these patients would have inadvertently masked important information on viral interactions. Finally, co-infection groups may have had higher viral loads prior to treatment initiation and would therefore have required more time to reach undetectable levels. Consequently, our results may have been biased in what appears as a lack of suppression, especially in HIVHBVHCVHDV co-infection. However, considering the multitude of treatments used and the varying time-points at which they were administered, dening a baseline viral load to adjust for would be difcult. In conclusion, an overall suppression of HBV was observed under HCV and HDV infection, in the presence of antiviral treatment among patients infected with HIV. Variations on these interactions still persist even in the presence of treatments. When comparing the detectability of HCV and HDV, HDV imposed a more dominant presence in quad-infection on HCV, which may have resulted in a reactivation of the HBVHCV reciprocal inhibition paradigm. 2009 Blackwell Publishing Ltd, 17, 6576

strongest at 12 months in HIVHBVHCVHDV vs HIV HBV co-infection, whereas at other time points, there was either minimal or even reverse inhibition. This dynamic shift may explain divergent cross-sectional results, especially in tri-infection with HBVHCVHDV, where both HDV and HCV have been shown to dominate over the replication of the respective hepatotropic viruses [2225]. The interactions of HCV and HDV replications in HIVHBV co-infection could also be examined among quad-infected patients, in whom a consistent level of high HDV and low HCV replication was observed during overall follow-up. HDV infection has been purported to induce an indirect, inhibitory response towards HCV via HDV-specic T cells [30], however it remains unclear by which mechanisms. Furthermore, both viruses respond differently to cytokines HCV replication can be efciently suppressed by interferon-a and interferon-c [31,32] while HDV has been shown to interfere with interferon-a signaling via the JAK-STAT pathway thereby reducing antiviral activity [33]. Other interferon-independent mechanisms have been known to inhibit HCV replication, such as Toll-like receptor 7 ligands located in hepatocytes [34], yet the implication of HDV on such pathways has not been studied. At any rate, HCV suppression may have also created yet another imbalance in the reciprocal interaction between HBV and HCV, as blips and rebounds in HBV and HCV treatmentresponse proles were observed among quad-infected patients. Past cross-sectional studies have been discordant on this interaction, nevertheless, most of the initial ndings have included low numbers of patients from the pre-HAART era [8,9,35] or in specialized populations, such as predominately IV-drug users [35] or haemophiliacs [36]. More recent cross-sectional evaluations yielded similar results to ours in HIV-negative [21,25,28] and HAART-treated, HIV-positive patients [1,37]. We also attempted to investigate virological interactions in the presence of antiviral treatments via response proles. HBV treatment-response proles were equivocally distributed when infected with HCV or HDV, suggesting that the patients treatment response to HBV-replication was not inuenced by co-infection. Treatment with adefovir or tenofovir may have been most successful at reducing HBV viral loads, whose efcacy has been previously described in HIVHBV co-infected patients even in the presence of HCV [38,39]. Standard interferon has been previously reported as ineffective in reducing serum HBV-DNA in HIVHBV co-infected patients [40], and the high proportion of YMDD mutations in our patients may have compromised any effect from lamivudine/emtricitabine. HBV proles did blip more frequently during HIVHBVHCVHDV infection possibly related to the increased variability of viral interaction over time. The efcacy of Peg-interferon and ribavirin therapy has been demonstrated in HIVHCV co-infection [4143] and may be similar in HIVHBVHCV and HIVHBVHCVHDV co-infected patients even under the suppressive effect of HDV-replication on HCV. HCV proles did however appear to

Hepatitis Viral Interactions in HIV Further studies on incident cases may help determine whether the order of viral hepatitis infections matters. In view of repeated periods of detectable and undetectable viral loads, viral quantications should be regularly performed over follow up before concluding on an inhibitory effect of multiple hepatitis viruses, especially in the context of HIV, where viral uctuations appeared to be very frequent. Physicians should keep in mind viral interactions when evaluating the patients prognosis and management, taking into account the viruses involved and the patients replication prole.

75

ACKNOWLEDGMENTS AND DISCLOSURES


The authors would like to sincerely thank all participants and staff dedicated to the French HIVHBV Cohort, espe` cially Pascale Tran, Nadege Algans, Manuela Sebire, and Fei Cao for their particular contribution to this study. We would also like to thank Drs. J. Michael Oakes and Stephen J. McSorley for their helpful comments on an earlier version of the manuscript.

STATEMENT OF INTEREST
This study was funded in part by SIDACTION with additional funding from the ANRS (Agence Nationale de Recherche sur le Sida). The French HIVHBV Cohort is sponsored by IMEA (Institut de Medecine et dEpidemiologie Appliquee), Paris, France. The authors report no conict of interests.

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